Many chemical compounds, particular chemical compounds that are useful in pharmacologic applications, are poorly soluble in water. Such drugs may be classified according to USP-NF as being sparingly soluble, slightly soluble, very slightly soluble, or insoluble in water. Many of these compounds are also poorly soluble in oils. An example of such a chemical compound includes the azole family of drugs, which family includes metronidazole, fluconazole, ketoconazole, itraconazole, miconazole, dimetridazole, secnidazole, ornidazole, tinidazole, carnidazole, and panidazole.
In many situations, such drugs may be formulated as a suspension, in which case the lack of solubility of the drug in water and in pharmaceutical oils does not typically have a negative impact on bioavailability. However, in situations where a solution of the drug is desired, or where an emulsion containing the drug in solution either in the hydrophilic or lipophilic phase of the emulsion is desired, the lack of solubility of the drug in water and oils provides a significant obstacle to obtaining desired concentrations of the drug.
The need to increase the aqueous solubility of poorly water soluble drugs that are also poorly soluble in oils is especially critical when formulating an emulsion, such as a topical cream, lotion, or ointment, containing such a drug. In this case, in order to obtain a sufficiently high concentration of the drug in the emulsion formulation as a whole, the concentration of the drug in the aqueous phase must be sufficiently elevated to overcome the lack of partitioning of the drug into the oil phase.
Metronidazole is an antimicrobial drug that is administered systemically for treatment of infections with anaerobic bacteria and protozoans, such as Trichomonas, Entamoeba, and Giardia. It is also used topically to treat bacterial vaginosis and various forms of acne, including acne rosacea. The aqueous solubility of metronidazole in water at room temperature is only about 0.87% w/w. Additionally, physically stable solutions of metronidazole in water that can withstand exposure to cold temperatures encountered during shipping are limited to about 0.7% w/w metronidazole. However, for many topical applications, a concentration of 1.0% or higher is desired.
The lack of solubility of such drugs, and the inability to obtain sufficiently high concentrations of drugs in solution in pharmaceutically acceptable carriers, is a serious problem in the formulation of topical therapeutic products for the treatment of medical conditions affecting the skin or mucosa. Such lack of solubility is additionally a concern in the formulation of medications for parenteral administration and for oral liquids that are often used for children and geriatric patients. Accordingly, a significant need exists for a method to increase the solubility of drugs that are poorly soluble in water, and especially those, like azole drugs such as metronidazole, that are also poorly soluble in pharmaceutical oils.